Cancer Immunology, Immunotherapy

, Volume 55, Issue 12, pp 1590–1600

Target-selective activation of a TNF prodrug by urokinase-type plasminogen activator (uPA) mediated proteolytic processing at the cell surface

  • Jeannette Gerspach
  • Julia Németh
  • Sabine Münkel
  • Harald Wajant
  • Klaus Pfizenmaier
Original Article

DOI: 10.1007/s00262-006-0162-6

Cite this article as:
Gerspach, J., Németh, J., Münkel, S. et al. Cancer Immunol Immunother (2006) 55: 1590. doi:10.1007/s00262-006-0162-6

Abstract

We have previously developed TNF prodrugs comprised of a N-terminal scFv targeting, a TNF effector and a C-terminal TNFR1-derived inhibitor module linked to TNF via a MMP-2 motif containing peptide, allowing activation by MMP-2-expressing tumor cells. To overcome the known heterogeneity of matrix metalloprotease expression, we developed TNF prodrugs that become processed by other tumor and/or stroma-associated proteases. These TNF prodrugs comprise either an uPA-selective or a dual uPA-MMP-2-specific linker which displayed efficient, target-dependent and cleavage sequence-specific activation by the corresponding tumor cell-expressed proteases. Selective pharmacologic inhibition of endogenous uPA and MMP-2 confirm independent prodrug processing by these two model proteases and indicate the functional superiority of a prodrug containing a multi-specific protease linker. Processing optimised TNF prodrugs should increase the proportion of active therapeutic within the targeted tissue and thus potentially enhance tumor response rate.

Keywords

Targeted TNF activationProdrug processinguPAMMP-2

Abbreviations

Ab

Antibody

FAP

Fibroblast activation protein

MMP

Matrix-metalloproteinase

TNF

Tumor necrosis factor

TNFR

TNF receptor

scFv 36

FAP-specific single chain variable fragment

uPA

Urokinase-type plasminogen activator

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Jeannette Gerspach
    • 1
  • Julia Németh
    • 1
  • Sabine Münkel
    • 1
  • Harald Wajant
    • 2
  • Klaus Pfizenmaier
    • 1
  1. 1.Institute of Cell Biology and Immunology University of StuttgartStuttgartGermany
  2. 2.Department of Molecular Internal Medicine, Medical Clinic and Polyclinic IIUniversity of WürzburgWurzburgGermany